Head and neck squamous cell carcinoma (HNSCC) is a debilitating and lethal disease. Despite significant advances in radiotherapy and surgical management, the 5-year survival rates have remained suboptimal. To improve therapeutic outcomes, better biomarkers and targeted therapeutic approaches are needed. Novel biomarkers can provide guidance for patient stratification and can optimize therapeutic strategy by improving patient survival and/or decreasing treatment-related toxicities. Although the recent focus on biomarkers for HNSCC has been on the human papilloma virus (HPV) status, additional efforts in improving the efficacy of individualized therapy have lead to the discovery of a number of promising epigenetic or genomic based markers as well as non-invasive functional imaging. One known cause of locoregional failure or distant metastasis after radiotherapy for HNSCC is tumor hypoxia. We propose that in tumors with positive HPV status and no hypoxia before radiotherapy or rapid resolution of tumor hypoxia (depicted by fluoromisonidazole positron emission tomography or 18F- FMISO PET) during treatment, a less intensive and less toxic regimen will yield the same tumor control as the standard 70Gy approach (intensity reduction or non- inferiority approach in Aim 1). To perform dose de-escalation in a safe manner, we propose to limit de-escalation to the node(s) of HPV+ HNSCC. All of these patients who underwent dose de-escalation to the node(s) will also undergo neck dissection as part of their treatment. On the other hand, HPV negative tumors with the presence of hypoxia before radiotherapy and with persistent hypoxia during treatment may require more aggressive therapy (intensity escalation or superiority approach). In Aim 2, we will determine using quantitative metrics between hypoxia 18F-FMISO image findings versus tumor treatment response in a HPV negative cohort. In Aim 3, we will conduct an imaging-pathological study to detail the spatial and temporal correlation between the evolution of 18F-FMISO imaging signal and change in hypoxia biomarker expression. Obtaining longitudinal profile of any given hypoxia biomarker will require repeated biopsies of tumors during a course of radiotherapy which in general has not been received well by the patient. Therefore, a priori using noninvasive 18F-FMISO PET is more appealing and practical. Confirmation of 18F-FMISO-biomarker correlation in Aim 3 will provide physicians a noninvasive avenue in selecting tumors likely to spread distantly for more intensive or novel therapy.